Biomedical subjects

S F Maier

Publications and source records attributed to S F Maier.

At least 19 recordsLinked to original sources

PubMed1997

Comparison of the effects of nucleus tractus solitarius and ventral medial medulla lesions on illness-induced and subcutaneous formalin-induced hyperalgesias.

We have previously demonstrated that illness-inducing agents (lipopolysaccharide (LPS)) and inflammatory agents (subcutaneous (s.c.) formalin) induce hyperalgesia by similar pathways. The present series of experiments compared the effects of medullary lesions on these phenomena. These experiments demonstrate that s.c. formalin-induced hyperalgesia, like illness-induced hyperalgesia, is dependent on the nucleus raphe magnus (NRM) but independent of the nucleus reticularis paragigantocellularis (NRPgc). However, these two forms of hyperalgesia differ with regards to their dependence on the nucleus tractus solitarius (NTS). Illness-induced hyperalgesia is abolished by unilateral (left) NTS lesions, whereas formalin-induced hyperalgesia remains unaffected by this procedure. These data provide further evidence that hyperalgesias induced by illness agents and by inflammatory agents are mediated by similar but not identical pathways. They also illustrate that neural structures have the capacity for opposed actions, in that both the NTS and NRM are documented to underlie hyperalgesia as well as analgesia. This capacity for opposed action may prove to be characteristic of structures involved in pain modulation.

Animals↗

PubMed1996

Associative and non-associative mechanisms of morphine analgesic tolerance are neurochemically distinct in the rat spinal cord.

Opiate tolerance involves both associative and non-associative changes. However, procedures designed to distinguish between these two processes have rarely been employed when investigating the physiological basis of such plasticity. The present experiments assessed some of the mechanisms contributing to both associative and non-associative decreases in morphine analgesic potency following repeated IV morphine administration (4 days, 5 mg/kg per day). For one group of rats, testing for morphine analgesia (tailflick) occurred in a context that had been repeatedly paired with morphine administration. Another group of rats, exposed equally to the testing context, handling procedures and morphine, was tested for morphine analgesia in a context that was specifically unpaired with prior drug. Although both of these groups showed a decrease in the drug effect following repeated administrations, those rats tested in the morphine-associated context were significantly more tolerant than the unpaired group. We evaluated the spinal cord involvement of NMDA receptors, as well as the peptide neurotensin in these two types of tolerance. NMDA receptors appeared to mediate non-associative changes in drug potency, as rats tested in either context were less tolerant when morphine administration was preceded with the non-competitive NMDA antagonist, MK-801 (2.5 and 5 nmol). Spinal neurotensin antagonism with [D-Trp11]neurotensin (3 pmol) selectively abolished associative tolerance. These findings provide information about the mechanisms of opiate tolerance and support the distinction between associative and non-associative processes underlying these changes.

Analgesics, Opioid↗

PubMed1996

Macrophage stimulation reduces the cholesterol levels of stressed and unstressed rats.

Male, Sprague-Dawley rats were either treated with zymosan, a nonspecific macrophage stimulator, or saline vehicle. Half of each group were then subjected to a stress procedure, the other half remained in their home cage. Results indicate that zymosan-treated animals had lower levels of total, low-density/very-low-density, and high-density lipoprotein than vehicle controls. Stressed animals had higher levels of the cholesterol parameters than did home cage controls. Manipulation of macrophage levels may be a prophylactic manipulation to combat stress-induced increases in cholesterol.

Animals↗

PubMed1996

Peripheral beta-adrenoreceptors and stress-induced hypercholesterolemia in rats.

Three experiments were conducted examining the contribution of beta-adrenergic receptors to stress-induced cholesterol increases. Rats were exposed to 3 90-min sessions of inescapable tailshock, or left undisturbed in their home cage. Propranolol, a nonselective beta-blocker, attenuated the stress-induced cholesterol increase when administered prior to the daily shock session. Atenolol, a beta-1 specific antagonist, also attenuated the stress-induced cholesterol increase. Butoxamine, a beta-2 specific antagonist, had no effect on the stress-induced cholesterol increases. Results are discussed in terms of catecholamine-stimulated free fatty acid (FFA) release as a potential mechanism for producing stress-induced hypercholesterolemia.

Adrenergic beta-Antagonists↗

PubMed1996

RU-486 blocks differentially suppressive effect of stress on in vivo anti-KLH immunoglobulin response.

Exposure to stressors can affect various aspects of immune function, including the antibody response. We have previously reported that rats exposed to an acute session of inescapable tail shock (IS) show long-term reductions in anti-keyhole limpet hemocyanin (KLH) immunoglobulin (Ig) M and IgG and a failure to expand Th1-like cells in response to KLH. To further investigate the potential role of decreased Th1-like cells in the IS-induced reduction of anti-KLH Ig, we examined two isotypes of IgG, IgG1 and IgG2a. Isotype switching is under cytokine control. Interleukin-4 helps B cells switch from making IgM to making IgG1, whereas interferon (IFN)-gamma helps B cells switch from making IgM to making IgG2a. In this paper we report that IS exposure reduces IFN-gamma levels 4 days after exposure to IS+KLH compared with immunized home cage controls. In addition, IS exposure reduced the Th1 cytokine-sensitive anti-KLH IgG2a but not Th2 cytokine-sensitive anti-KLH IgG1. This pattern of isotype reduction suggests that a failure to expand the Th1 cell, which results in less IFN-gamma, may contribute to the the IS-induced reduction in anti-KLH Ig. Glucocorticoids (GCs) differentially regulate Th1 and Th2 cells. Administration of the type II GC receptor antagonist RU-486 before IS blocked the IS-induced suppression in anti-KLH IgM, IgG, and IgG2a. Corticosterone (2.5 mg/kg), however, did not produce the suppression in anti-KLH Ig. These results support a role of corticosterone in mediating IS-induced reductions in in vivo antibody.

Adjuvants, Immunologic↗

PubMed1996

Morphine-induced alterations in antibody levels: receptor and immune mechanisms.

We have previously shown that an acute administration of morphine (10 mg/kg, i.v.) decreases IgG, but not IgM, antibody levels to antigen administered before morphine. Further, decreases in IgG were blocked by previous administration of naltrexone, indicating that receptor binding is critical to the decreased antibody levels. These studies investigated potential receptor and immune mechanisms for these effects. To investigate potential receptor mechanisms, the stereoselectivity and location of receptor binding was determined. The results of these experiments suggest morphine must bind stereoselectively to central sites to decrease antibody levels after antigen administration. To investigate potential immune mechanisms for these changes, antibody secreting cells (ASC) for keyhole limpet hemocyanin-specific IgG and IgM were enumerated. Morphine decreased ASC for IgG but increased ASC for IgM. Two pathways for the genetic switch from IgM to IgG production were investigated. One pathway requires interferon-gamma to stimulate IgM-secreting cells to switch to IgG2a-secreting cells. Another pathway requires interleukin-4 to stimulate IgM-secreting cells to switch to IgG1- secreting cells. IgG1 and IgG2a levels were measured to determine if these pathways were differentially affected and only IgG2a levels were decreased. Further, these decreases were accompanied by decreased IFN-gamma levels but not by altered numbers of splenocytes. These data indicate that morphine may alter the ability of ASC to switch from IgM to IgG2a production, possibly by reducing the availability of IFN-gamma.

Animals↗

PubMed1995

Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock.

Brain interleukin-1 (IL-1) plays a key role in mediating the neural, endocrine, and behavioral consequences of injury and infection. Recent evidence indicates that brain IL-1 may also be important in producing endocrine and neurochemical responses to stressors. The present experiment sought to determine whether intracerebroventricular (i.c.v.) administration of an interleukin-1 receptor antagonist (IL-1ra) would block behavioral effects of a stressor. I.c.v. application of hrIL-1ra before inescapable shock blocked the subsequent interference with escape learning and enhancement of fear conditioning normally produced by this treatment.

Animals↗

PubMed1995

Mechanisms of tumor necrosis factor-alpha (TNF-alpha) hyperalgesia.

Activation of immune cells by pathogens induces the release of a variety of proinflammatory cytokines, including IL-1 beta and TNF-alpha. Previous studies using IL-1 beta have demonstrated that this cytokine can alter brain function, resulting in a variety of 'illness responses' including increased sleep, decreased food intake, fever, etc. We have recently demonstrated that i.p. IL-1 beta also produces hyperalgesia and that this hyperalgesia (as well as most illness responses) is mediated via activation of subdiaphragmatic vagal afferents. The present series of studies were designed to provide an initial examination of the generality of proinflammatory cytokine-induced hyperalgesia by examining the effects of i.p. TNF-alpha on pain responsivity. These studies demonstrate that: (a) i.p. TNF-alpha produces dose-dependent hyperalgesia as measured by the tailflick test, (b) this hyperalgesia is mediated via the induced release of IL-1 beta, (c) hyperalgesia is mediated via activation of subdiaphragmatic vagal afferents, and (d) the effects of subdiaphragmatic vagotomy cannot be explained by a generalized depression of neural excitability.

Animals↗

PubMed1995

Blockade of cytokine induced conditioned taste aversion by subdiaphragmatic vagotomy: further evidence for vagal mediation of immune-brain communication.

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are cytokines released by activated immune cells. IL-1 beta and TNF-alpha elicit various illness symptoms including avoidance of novel tastes with which they have been paired (conditioned taste aversion). Previous hypotheses to account for these actions have focused on blood-borne IL-1 beta and TNF-alpha exerting their effects directly at the brain. However, recent evidence suggests that these cytokines may activate subdiaphragmatic vagal afferents. The present experiments demonstrate that subdiaphragmatic vagal transection both attenuates acquisition and facilitates extinction of conditioned taste aversions induced by i.p. administration of either IL-1 beta or TNF-alpha.

Animals↗

PubMed1995

Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication.

Interleukin-1 beta (IL-1 beta), a cytokine released by activated immune cells, elicits various illness symptoms including hyperthermia. Previous hypotheses to account for these actions have focused on blood-borne IL-1 beta exerting its effects directly at the level of the brain. However, recent behavioral and physiological evidence suggest that IL-1 beta can activate the subdiaphragmatic vagus. The present experiments demonstrate that subdiaphragmatic vagal transection disrupts the hyperthermia-inducing effects of recombinant human IL-1 beta and stress. These data provide evidence for a novel route of immune-brain communication, as well as a novel route whereby stress can influence physiological processes.

Animals↗

PubMed1995

Stressed rats fail to expand the CD45RC+CD4+ (Th1-like) T cell subset in response to KLH: possible involvement of IFN-gamma.

Exposure to stressors effects various aspects of immune function, including the in vivo antibody response. We have previously reported that rats exposed to an acute session of inescapable tail shock (IS) show long-term reductions in anti-KLH (keyhole limpet hemocyanin) IgM and IgG. The mechanisms responsible for this suppression are currently unknown. Previous work has suggested changes in CD4+ T cells could be important. We report here that exposure to IS results in a reduction in Con A-stimulated IFN-gamma levels in mesenteric lymphocytes and splenocytes taken immediately after IS termination. In addition, IS exposure prevents the KLH-induced increase in the number of CD45RC+CD4+ T cells (Th1-like) in both the mesenteric lymph nodes and the spleen 4 days after immunization. The failure of KLH to expand the CD45RC+CD4+ subset could be due to the stress-induced reduction in IFN-gamma levels reported in cells taken at the time of immunization. Implications of these findings as a mechanism for the decrease in the in vivo antibody response previously reported is discussed.

Animals↗

PubMed1995

The benzodiazepine receptor antagonists flumazenil and CGS8216 block the enhancement of fear conditioning and interference with escape behavior produced by inescapable shock.

Prior work has suggested that the mediation of the behavioral effects of inescapable shock (IS) might involve release of an endogenous beta-carboline-like ligand at the dorsal raphe nucleus (DRN) that binds to the benzodiazepine (BZ) recognition site on the GABAA complex, thereby disinhibiting the DRN. This was tested by microinjection of the BZ receptor antagonists flumazenil and CGS8216 in the region of the DRN, either before IS or before later behavioral testing. Both compounds blocked subsequent enhancement of fear conditioning and interference with shuttlebox escape when administered before IS, but had no effect when given before testing. In addition, flumazenil did not alter the behavior of escapably shocked subjects.

Animals↗

PubMed1995

Cytokine-to-brain communication: a review & analysis of alternative mechanisms.

It is becoming well accepted that products of the immune system (cytokines) can signal the brain that infection has occurred. This cytokine-to-brain communication can result in marked alterations in brain function and behavior. This review examines alternative mechanisms that have been proposed to explain how such immune products can reach the brain via the blood to cause centrally-mediated "illness" responses. Finally, we describe a new view which argues that cytokines signal brain in quite a different manner, by stimulating afferent terminals of peripheral nerves at local sites of synthesis and release.

Afferent Pathways↗

PubMed1995

The elevated plus-maze is not sensitive to the effect of stressor controllability in rats.

The present experiments examined the sensitivity of the elevated plus-maze to the effects of stressor controllability. Previous work had established that inescapable but not an equal amount of escapable electric tail shock reduced social interaction. The present experiments demonstrate that prior exposure to shock alters elevated plus-maze behavior, but that this effect is not sensitive to the escapability of the shock. These experiments include a replication of the usual pharmacologic effects of benzodiazepine ligands (2 mg/kg diazepam; 0.4 mg/kg methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) to demonstrate the sensitivity of the elevated plus-maze procedures used. The results provide additional support for the idea that the social interaction and elevated plus-maze measures of "anxiety" are sensitive to different processes.

Animals↗

PubMed1995

Stress-induced reduction in the rat mixed lymphocyte reaction is due to macrophages and not to changes in T cell phenotypes.

Exposure to aversive events or stressors modulates various aspects of immune function. We have previously reported that exposure to an acute stressor, inescapable tail shock (IS), resulted in a shift in T cell subpopulations in rat mesenteric lymph nodes but not in cervical lymph nodes (Fleshner et al. (1992) J. Neuroimmunol. 41, 131-142). The mesenteric CD4+/CD8+ ratio was increased immediately after exposure to IS and was due primarily to an increase in the percent of CD4+ cells. The present experiments were designed to determine the relationship between the IS-associated phenotypic shift and its significance in the function of CD4+ T cells. The function assessed was the in vitro proliferative response to alloantigens coded for by the Major Histocompatibility Complex (MHC). Using the mixed lymphocyte reaction (MLR), we report that exposure to IS resulted in a decrease in the MLR response of cells from both cervical and mesenteric lymph nodes. Depletion of macrophages (nylon wool adherent cells) eliminated the IS-induced reduction and co-culture of macrophages (irradiation-insensitive cells) from shocked rats produced the suppression. One interpretation of these data is that exposure to IS resulted in the activation of macrophages and the release of a suppressive factor which reduced the MLR response of peripheral lymph node lymphocytes.

Animals↗

PubMed1995

Interleukin-1 beta induced corticosterone elevation and hypothalamic NE depletion is vagally mediated.

Processes occurring within the immune system can alter neural function. Cytokines released by cells of the immune system during illness are key messengers in immune-to-brain communication. Interleukin-1 beta (IL-1 beta) is particularly important in this regard and is known to stimulate a myriad of illness-related outcomes such as fever, sickness behavior, aphagia, adipsia, hypothalamic-pituitary-adrenal activation, and changes in pain reactivity. Thus peripherally released IL-1 beta has potent neural effects and is a critical mediator of the impact of immune processes on brain. There is, however, uncertainty concerning the communication pathways involved. We provide evidence that a primary route of peripheral cytokine signalling is through stimulation of peripheral vagal afferents rather than or in addition to direct cytokine access to brain. Subdiaphragmatic, but not hepatic vagotomy, blocked rhIL-1 beta-induced hypothalamic norepinephrine depletion and attenuated rhIL-1 beta-induced increases in serum corticosterone. These data suggest that rhIL-1 beta activates the hypothalamic-pituitary-adrenal axis via stimulation of peripheral vagal afferents and further support the hypothesis that peripheral cytokine signalling to the CNS is mediated primarily by stimulation of peripheral afferents.

Animals↗

PubMed1995

8-OH-DPAT microinjected in the region of the dorsal raphe nucleus blocks and reverses the enhancement of fear conditioning and interference with escape produced by exposure to inescapable shock.

Prior work suggests that inhibition of the dorsal raphe nucleus (DRN) either during exposure to inescapable electric shock (IS) or during later behavioral testing might block the usual behavioral consequences of IS. The 5-HT1A agonist 8-OH-DPAT was microinjected into the region of the DRN either before exposure to IS or before testing for fear conditioning and escape learning conducted 24 hr later. IS potentiated fear conditioning and interfered with escape performance. These effects were completely prevented by intra-DRN administration of 8-OH-DPAT at either point. Low but not high systemic doses of 8-OH-DPAT had a similar effect, supporting the idea that the effective site of action is presynaptic. The relation between these data and other effects of 8-OH-DPAT is discussed.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1995

The dorsal raphe nucleus is a site of action mediating the behavioral effects of the benzodiazepine receptor inverse agonist DMCM.

Systemic administration of benzodiazepine receptor inverse agonists leads to behavioral changes similar to those produced by inescapable shock (IS). The dorsal raphe nucleus (DRN) is a critical structure mediating IS effects. The present experiments determined whether the DRN is a site mediating the behavioral changes produced by benzodiazepine receptor inverse agonists. Microinjection of the inverse agonist Methyl 6,7-Dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in the region of the DRN produced enhancement of fear conditioning as assessed by the amount of freezing in the presence of shock cues as well as interference with shuttlebox escape learning assessed 24 hr later. Furthermore, lesion of the DRN blocked the effects of systemic DMCM on fear conditioning and escape learning. These data suggest that the DRN is indeed critical in mediating these behavioral consequences of DMCM and further support a role for the DRN in producing the behavioral changes induced by IS.

Animals↗